Estrogen–Estrogen Receptor α Signaling Facilitates Bilirubin Metabolism in Regenerating Liver Through Regulating Cytochrome P450 2A6 Expression

Abstract

Background: After living donor liver transplantation (LDLT), rising serum bilirubin levels commonly indicate insufficient numbers of hepatocytes are available to metabolize bilirubin into biliverdin. Recovery of bilirubin levels is an important marker of hepatocyte repopulation after LDLT. Cytochrome P450 (CYP) 2A6 in humans (or cyp2a4 in rodents) can function as “bilirubin oxidase.” Functional hepatocytes contain abundant CYP2A6, which is considered a marker for hepatocyte function recovery. The aim of our study was to determine the impact of estradiol/estrogen receptor signaling on bilirubin levels during liver function recovery. Methods: We conducted a hospital-based cohort study of bilirubin levels after LDLT surgery in both liver graft donors and recipients, performed a transcriptome comparison of wild-type versus estrogen receptor (ER)α knockout mice and a bioinformatics analysis of transcriptome changes in their regenerating liver after two-third partial hepatectomy (PHx), and assayed in vitro expression of cytochrome (CYP2A6) in human hepatic progenitor cells (HepRG) treated with 17β-estradiol (E2). Results: The latency of bilirubin level reduction was shorter in women than in men, suggesting that a female factor promotes bilirubin recovery after liver transplantation surgery. In the PHx mouse model, the expression of the cyp2a4 gene was significantly lower in livers from the knockout ERα mice than in livers from their wild-type littermates; but the expression of other bilirubin metabolism–related genes were similar between these groups. Moreover, E2 or bilirubin treatments significantly promoted CYP2A6 expression in hepatocyte progenitor cells (HepRG cells). Sequence analysis revealed similar levels of aryl hydrocarbon receptor (AhR; bilirubin responsive nuclear receptor) and ESR1 binding to the promoter region of CYP2A6. Conclusions: This is the first report to demonstrate, on a molecular level, that E2/ERα signaling facilitates bilirubin metabolism in regenerating liver. Our findings contribute new knowledge to our understanding of why the latency of improved bilirubin metabolism and thereby liver function recovery is shorter in females than in males.